This invention relates to novel cyanophenyl derivatives useful as medicaments, particularly as an anti-androgen, and salts and pharmaceutical compositions thereof.
Androgen as a steroid hormone is secreted from testis and adrenal cortex and induces male sex hormone actions. Androgen, when incorporated into target cells, acts upon an androgen receptor and the receptor to which androgen binds forms a dimer. Subsequently, this dimer binds to an androgen-response-element on DNA to accelerate synthesis of mRNA and to thereby induce proteins which control the androgen actions, thus expressing various actions within living organism (Prostate Suppl., 6, 1996, 45-51, Trends in Endocrinology and Metabolism, 1998, 9 (8), 317-324).
Prostatic cancer, benign prostatic hyperplasia, virilism, hirsutism, baldness, acne, seborrhea and the like can be exemplified as diseases which are progressed by androgen. Accordingly, anti-androgens are used for the treatment of these diseases in which androgen is concerned.
Anti-androgens, which have substrate resembling steroidal structure or nono-steroidal structure are currently used in the clinical field. Though chlormadinone acetate and the like are known as the steroidal anti-androgen, it is known that, since separation of actions of these compounds from other steroids having similar structures is not sufficient, they cause changes in the blood hormone level and induces serious side effects such as reduction of libido and the like (Jpn. J. Clin. Oncol., 1993, 23 (3), 178-185). On the other hand, flutamide (JP-A-49-81332; the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d), bicalutamide (GB 8221421, WO 95/19770) and the like acylanilide derivatives are known as non-steroidal anti-androgens, but their anti-androgenic actions are not sufficient. Thus, combined therapy with an LH-RH agonist is usual for the treatment of prostatic cancer (Nipponrinsho, 1998, 56 (8), 2124-2128).
Regarding the compounds having piperazinocyanophenyl skeletons, substances having oxitocin and vasopressin receptor antagonism are disclosed in WO 95/25443, and substances having 5HT receptor antagonism in WO 96/02525, substances as intercellular mutual action inhibitors in DE 4234295, substances as production intermediates of cell adhesion inhibitors in WO 97/2245 and substances having antitumor actions in WO 98/00402 and WO 98/21648, but they do not disclose or suggest on anti-androgen actions.
The object of the invention is to provide a novel cyanophenyl derivative and salts thereof having strong anti-androgen actions and to further provide medicaments containing the same.
With the aim of solving the aforementioned problems incidental to the existing anti-androgens, the inventors of the invention have conducted intensive studies and found unexpectedly that a novel cyanophenyl derivative to which a substituted carbamoyl or substituted sulfamoyl group is bound has strong anti-androgen actions and good oral activities, thus resulting in the accomplishment of the invention.
Accordingly, the invention relates to a cyanophenyl derivative represented by the following general formula (I) or a salt thereof 
wherein each symbol has the following meaning,
R: cyano or nitro group,
R1: a hydrogen atom, a halogen atom or a cyano, halogeno-lower alkyl, vitro, carboxyl, lower alkyl, R6xe2x80x94Axe2x80x94, R7xe2x80x94S(O)pxe2x80x94, lower alkyl-C(xe2x95x90O)xe2x80x94 or lower alkyl-Oxe2x80x94C(xe2x95x90O)xe2x80x94 group,
R2, R3 and R4: these may be the same or different from one another and each means a hydrogen atom, a lower alkyl group, a carbamoyl group which may be substituted by 1 or 2 lower alkyl groups, a lower alkyl-C(xe2x95x90O)xe2x80x94, lower alkyl-Oxe2x80x94C(xe2x95x90O)xe2x80x94 group, wherein R2 and R3 bind to optional carbon atoms on the ring,
R5: a lower alkyl; aryl-lower alkyl-Oxe2x80x94; carboxyl; lower alkyl-Oxe2x80x94C(xe2x95x90O)xe2x80x94; amido which may be substituted by 1 or 2 lower alkyl groups; or aryl, heterocyclic or cycloalkyl group which may have a substituent group; N(R13)R14-lower alkyl-Oxe2x80x94; with the proviso that when m=1, R4 and R5 may together form a five- or six-membered heterocycle which may have other hetero atom,
R6: a halogeno-lower alkyl; aryl; or lower alkyl which may be substituted by N(R)R10, OH or lower alkyl-Oxe2x80x94,
R7: a lower alkyl, aryl or N(R11)R12xe2x80x94,
R8, R9, R10, R11, R12, R13 and R14: hydrogen, lower alkyl or aryl, with the proviso that R6 and R8, R9 and R10 or R13 and R14 may together form a nitrogen-containing cycloalkyl which may have other hetero atom and may have la substituent group,
k or n: 1, 2 or 3,
m: 0 or 1,
p: 0, 1 or 2,
A: an oxygen atom or NR8,
Xxe2x95x90xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90S)xe2x80x94 or xe2x80x94S(O)2xe2x80x94 group,
Y: a bond, lower alkylene, xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94 group,
with the proviso that, when R5 is a lower alkyl group, Y is a group other than lower alkylene, and Z1 or Z2: these may be the same or different from each other and each means CH or nitrogen atom,
with the proviso that 1) when R1 is hydrogen atom, at least one of R2 and R3 is a lower alkyl, 2) when R is a nitro group, X is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94, and n is 1, k is 2 and m is 0, at least one of R2 and R3 is a group other than a hydrogen atom, and 3) when R is a cyano group, Z1 is a nitrogen atom, and X is xe2x80x94C(xe2x95x90O)xe2x80x94 and n is 1, k is 2, m is 0, and R5 is a methyl group, R1 is a group other than a fluorine atom.
Preferred is a cyanophenyl derivative or a salt thereof according to the first aspect of the invention, wherein R is a cyano group;
also preferred is a cyanophenyl derivative or a salt thereof according to the first aspect of the invention, wherein R1 is a halogen atom, cyano, halogeno-lower alkyl, nitro or lower alkyl-Oxe2x80x94; R2 and R3: at least one of them is a lower alkyl group; R4: a hydrogen atom or a lower alkyl group; R5: an aryl, heterocyclic or cycloalkyl group which may have substituent(s) group; k is 2, n is 1; m is 1, X is xe2x80x94C(xe2x95x90O)xe2x80x94 group; Y is a bond; and Z1 or Z2 both means CH;
more preferred is a cyanophenyl derivative according to the first or second aspect of the invention, wherein the substituent group of the aryl, heterocyclic or cycloalkyl group of R5 which may have substituent(s) is a radical selected from the group consisting of a halogen atom, halogeno-lower alkyl, lower alkyl, lower alkyl-Oxe2x80x94, lower alkyl-Sxe2x80x94, lower alkyl-S(xe2x95x90O)xe2x80x94, lower alkyl-S(O)2xe2x80x94, sulfamoyl which may be substituted by 1 or 2 lower alkyl groups, halogeno-lower alkyl-Oxe2x80x94, cyano, nitro, oxo(xe2x95x90O), lower alkyl-C(xe2x95x90O)xe2x80x94, aryl-C(xe2x95x90O)xe2x80x94, amino which may be substituted by 1 or 2 of lower alkyl or lower alkyl-C(xe2x95x90O)xe2x80x94 or lower alkyl-O-C(xe2x95x90O)xe2x80x94, aryl-Oxe2x80x94, amino-Oxe2x80x94, carbamoyl which may be substituted by a lower alkyl, carboxyl, lower alkyl-Oxe2x80x94 C(xe2x95x90O)xe2x80x94, heterocyclic and OH group; and
most preferred is a compound, or a salt thereof, selected from (2R,5S)4-(4-cyano-3-trifluoromethylphenyl)-N-(6-methoxy-3-pyridyl)-2,5-dimethylpiperazine-1-carboxamide; (2R,5S)-N-(2-amino-pyrimidin-4-yl)-4-(4-cyano-3-trifluoromethylphenyl)-2,5-dimethylpiperazine-1-carboxamide; (2R,5S)-4-(4-cyano-3-trifluoromethylphenyl)-2,5-dimethyl-N-(6-trifluoromethyl-3-pyridyl)piperazine-1-carboxamide; (2R,5S)-4-(4-cyano-3-trifluoromethylphenyl)-N-(2-fluoro-4-pyridyl)-2,5-dimethylpiperazine-1-carboxamide; and (2R,5S)-N-(2-bromo-4-pyridyl)-4-(4-cyano-3-trifluoromethylphenyl)-2,5 -dimethylpiperazine-1-carboxamide.
Another object of the invention is a pharmaceutical composition which comprises the cyanophenyl derivative of general formula (I) or a salt thereof as the active ingredient;
preferably an anti-androgen agent which comprises the cyanophenyl derivative of general formula (I) or a salt thereof as the active ingredient; and
more preferably a therapeutic agent for diseases which are progressed by androgen, which comprises the cyanophenyl derivative of general formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient, wherein the diseases which are progressed by androgen include prostatic cancer, benign prostatic hyperplasia, virilism, hirsutism, baldness, acne and seborrhea.
Most preferred is a pharmaceutical composition for the treatment of prostatic cancer and benign prostatic hyperplasia, which comprises the cyanophenyl derivative of general formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient.
The following further describes the compound represented by general formula (I).
In the definition of general formula of the invention, the term xe2x80x9clowerxe2x80x9d means a straight or branched carbon chain having from 1 to 6 carbon atoms unless otherwise noted.
The group R2 or R3 binds to the same or different optional carbon atom on the saturated ring containing two nitrogen atoms.
The aryl, heterocyclic or cycloalkyl group which may have a substituent group may have from 1 to 3 substituent groups on the ring, preferably a halogen atom, halogeno-lower alkyl, lower alkyl, lower alkyl-Oxe2x80x94, lower alkyl-Sxe2x80x94, lower alkyl-S (xe2x95x90O)xe2x80x94, lower alkyl-S(O)2xe2x80x94, sulfamoyl which may be substituted by 1 or 2 lower alkyl groups, halogeno-lower alkyl-Oxe2x80x94, cyano, nitro, oxo(xe2x95x90O), lower alkyl-C(xe2x95x90O)xe2x80x94, aryl-C(xe2x95x90O)xe2x80x94, amino which may be substituted by 1 or 2 of lower alkyl or lower alkyl-C(xe2x95x90O)xe2x80x94 or lower alkyl-Oxe2x80x94C(xe2x95x90O)xe2x80x94, aryl-Oxe2x80x94, amino-Oxe2x80x94, carbamoyl which may be substituted by 1 or 2 lower alkyl or carboxyl or lower alkyl-Oxe2x80x94C(xe2x95x90O)xe2x80x94, heterocycle which may have a substituent group or OH group.
The xe2x80x9clower alkylxe2x80x9d is desirably a straight or branched-chain lower alkyl group having from 1 to 6 carbon atoms, and its examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
As substituent group of the lower alkyl-Oxe2x80x94 which may have a substituent group, aryl group or the like substituent group can be exemplified.
The xe2x80x9clower alkylenexe2x80x9d is desirably a straight or branched-chain lower alkylene group having from 1 to 6 carbon atoms, and its examples include methylene, ethylene, propylene, isopropylene, butylene, pentamethylene, hexamethylene and the like, of which an alkylene having from 1 to 3 carbon atoms is preferred.
The xe2x80x9carylxe2x80x9d is desirably an aromatic hydrocarbon radical having from 6 to 12 carbon atoms, and its examples include phenyl, xcex1-naphthyl, xcex2-naphthyl, biphenylyl and the like. More preferred are those which have from 6 to 10 carbon atoms.
As the xe2x80x9chalogen atomxe2x80x9d, fluorine, chlorine, bromine or iodine atom can be defined.
The aforementioned C1-6 alkyl group is desirable as the lower alkyl group of the xe2x80x9chalogeno-lower alkylxe2x80x9d, and examples of the halogeno-C1-6 alkyl group include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-iodoethyl and the like, of which trifluoromethyl is preferred.
The xe2x80x9ccycloalkyl groupxe2x80x9d is desirably a three- to eight-membered alicyclic hydrocarbon radical having from 3 to 10 carbon atoms, and its examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The xe2x80x9cheterocyclexe2x80x9d means a five- or six-membered heteroaryl group or saturated heterocycle containing from 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, or a bicyclic heteroaryl group condensed with benzene ring or other heterocycle, and examples of the heteroaryl group include pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, thiophene, thiopyran, furan, pyran, dioxolane, thiazole, isothiazole, thiadiazole, thiazine, oxazole, isoxazole, oxadiazole, furazane, dioxazole, oxazine, oxadiazine, dioxazine and the like, examples of the saturated heterocycle include pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholyl group, thiomorpholyl group and the like, and examples of the condensed heteroaryl include indole, isoindole, indazole, quinoline, quinazoline, quinoxaline, isoquinoline, benzimidazole, benzothiophene, benzothiazole, benzofuran, benzofurazane, imidazopyridine, imidazopyrazine, pyridopyridine, phthalazine, naphthyridine, indolizine, purine, quinolizine, cinnoline, isochroman, chroman and the like. Preferred is pyridine, pyrimidine, thiophene, furan or the like five- or six-membered heteroaryl group having 1 or 2 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom.
The term xe2x80x9cwhen m=1, R4 and R5 may together form a five- or six-membered heterocycle which may have other hetero atomxe2x80x9d means a five- or six-membered heteroaryl group or saturated heterocycle having from 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and it may have oxo group or the like substituent group. Illustratively, examples of the heteroaryl include pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole and the like, and examples of the saturated heterocycle include pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholyl group, thiomorpholyl, 1,4-diazepan, thiomorpholine-1-oxido, thiomorpholine-1,1-dioxido, 1,4-oxazepan group and the like. Preferred is a five- or six-membered saturated heterocycle having 1 hetero atom selected from nitrogen atom, oxygen atom and sulfur atom, in addition to the nitrogen atom to which R4 is bonded, and more preferred in thiomorpholino group.
The term xe2x80x9cR6 and R8, R9 and R10 or R13 and R14 can together form a nitrogen-containing cycloalkyl which may have other hetero atom and may have substituent group(s)xe2x80x9d means a five- or six-membered saturated heterocycle having 1 hetero atom selected from nitrogen atom, oxygen atom and sulfur atom, in addition to the nitrogen atoms to which R6 and R8, R9 and R10 or R13 and R14 are bonded, and it may also have 1 or 2 substituent groups such as oxo group, lower alkyl, aryl and the like. Preferred is pyrrolidino, piperidino, morpholino, piperazine or thiomorpholino group.
Among the compounds of the invention, in the case of a compound which has a tertiary amine or sulfide, the nitrogen atom or sulfur atom may be converted into oxido at an appropriate oxidation state, and all of these oxido derivatives are included herein.
Geometrical isomers based on the amido bond exist in the compound (I) of the invention. Depending on the kind of substituent group, it may have an asymmetric center or axial asymmetry of one or more carbon, nitrogen, sulfur and the like in some cases, and (R) isomer, (S) isomer and the like optical isomers, racemic modification, diastereomers and the like exist based thereon. Also, depending on the kind of substituent group, it may have double bond, so that geometrical isomers such as (Z) isomer, (E) isomer and the like, as well as cis-form and trans-form based on cyclohexane and the like, are present. All of the separated or mixed form of these isomers are included in the invention.
The compound of the invention forms a salt. Illustratively, it is an acid addition salt with an inorganic acid or an organic acid or a salt with an inorganic or organic base, and a pharmaceutically acceptable salt is desirable. Illustrative examples of the salt include addition salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like mineral acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like organic acids or aspartic acid, glutamic acid and the like acidic amino acids, and salts with sodium, potassium, magnesium, calcium, aluminum, lithium and the like inorganic bases, methylamine, ethylamine, ethanolamine and the like organic bases or lysine, ornithine and the like basic amino acids. It may also be in the form of a quaternary ammonium salt. Illustrative examples of the quaternary ammonium salt include a lower alkyl halide, a lower alkyl triflate, a lower alkyl tosylate, a benzyl halide and the like, of which methyl iodide, benzyl chloride or the like is preferred.
In addition, the compound of the invention can form a hydrate, a solvate with ethanol or the like and polymorphism.
(Production Methods)
First production method 
(Symbols in the formula are as defined in the foregoing.)
This production method is a method in which the compound (I) of the invention is produced by allowing a substituted amine represented by the general formula (II) or a salt thereof to react with a compound represented by the general formula (III) or a reactive derivative thereof and then, if there is a protecting group, removing the protecting group.
Examples of the reactive derivative of the compound (III) include usual carboxylic acid esters such as methyl ester, ethyl ester, isobutyl ester, tert-butyl ester and the like; its phenylesters such as p-nitrophenyl ester and the like; its acid halides such as chloride, acid bromide and the like, acid azide, its active esters obtained by allowing it to react with a phenolic compound such as 2,4-dinitrophenol and the like phenol compounds or 1-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBt) and the like N-hydroxyamine compounds; its symmetric anhydrides; its mixed acid anhydrides including organic acid based mixed acid anhydrides obtained by reacting with acid anhydrides, alkyl carboxylate halide and the like halocarboxylic acid alkyl esters or pivaloyl halides, and phosphoric acid based mixed acid anhydrides obtained by the combination of triphenylphosphine and the like organic phosphorus compounds with N-bromosuccinimide and the like activating agents, as well as sulfonyl chloride and isocyanate.
In addition, when a carboxylic acid is allowed to react as free acid or an active ester is allowed to react without isolation, it is desirable to use dicyclohexylcarbodiimide (DCC), carbonyldiimidazole, diphenylphosphoryl azide, diethylphosphoryl cyanide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) or the like condensing agent.
According to the invention, an acid chloride method, a method in which the reaction is carried out in the coexistence of an active esterification agent and a condensation reaction with an isocyanate or a thioisocyanate are particularly advantageous.
In this connection, the isocyanate can be synthesized from a carboxylic acid, an amide, an acid hydrazide or the like carboxylic acid derivative making use of a known rearrangement reaction. When converted into isocyanate from a carboxylic acid, it is advantageous to use a method in which the carboxylic acid is once converted into an acid chloride, a mixed acid anhydride or the like and then allowed to react with sodium azide or the like to obtain an acid azide which is subsequently converted into an isocyanate by heating or the like means. Also, when diphenylphosphoryl azide (DPPA) is used in this method, it is possible to convert the carboxylic acid into an isocyanate by one reaction. It is also possible to obtain the compound (I) by allowing DPPA to undergo the reaction in the coexistence of the carboxylic acid and compound (II). On the other hand, it is possible to obtain isocyanate by allowing a corresponding amine derivative to react with phosgene or a phosgene-equivalent compound. Examples of the phosgene-equivalent compound include phosgene dimer, triphosgene, carbonyldiimidazole and a combination of di-tert-butyl carbonate (DIBOC) with 4-(N,N-dimethylamino)pyridine (DMAP). Also, the thioisocyanate can be synthesized making use of a known reaction using thiophosgene, thiocarbonyldiimidazole or the like.
In addition, it is possible to obtain the compound (I) by once converting a corresponding amine derivative into an active intermediate having a leaving group typified by phenyl carbonate and then allowing it to react with the compound (II).
Though it varies depending on the used reactive derivative, condensing agent and the like, the reaction is generally carried out in an inert organic solvent including dichloromethane, dichloroethane, chloroform and the like halogenated hydrocarbons, benzene, toluene, xylene and the like aromatic hydrocarbons, ether, tetrahydrofuran and the like ethers, ethyl acetate and the like esters, acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methylpyrrolidone, dimethylimidazolidinone and the like, under cooling, under cooling to room temperature or under room temperature to heating, depending on the reactive derivative.
In carrying out the reaction, in order to progress the reaction smoothly, it is advantageous in some cases to use the substituted amine (II) in excess amount or to carry out the reaction in the presence of N-methylmorpholine, trimethylamine, triethylamine, N,N-dimethylaniline, pyridine, DMAP, picoline, lutidine, collidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or the like base. Pyridine or the like can also be used as the solvent.
In this case, it is desirable in some cases that the oxygen, sulfur, nitrogen or the like atom existing in the molecule is bonded with a protecting group, and the protecting groups described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, second edition, edited by Greene and Wuts, can be exemplified as the protecting group and used by optionally selecting them depending on the reaction conditions.
Second production method 
(Symbols in the formula are as defined in the foregoing.)
This production method is a method in which the compound (I) of the invention is produced by allowing a substituted amine represented by the general formula (II) or a salt thereof to react with an X-containing or equivalent reactive compound and then to react with a compound represented by the general formula (IV), subsequently removing a protecting group if there is a protecting group.
When the product is a urea derivative, phosgene, phosgene dimer, triphosgene, carbonyldiimidazole or a known equivalent compound can be used as the X-containing or equivalent reactive compound. When the product is a sulfamide derivative, sulfamide, sulfuryl chloride or the like known reagent can be used.
In carrying out the reaction, the conditions shown in the first production method can be employed.
Third production method 
(In the formula, Q means fluorine, chlorine, bromine, iodine or the like halogen or trifluoromethane sulfonate, benzene sulfonate or the like leaving group.)
This production method is a method in which the compound (I) of the invention is produced by allowing a substituted amine represented by the general formula (VI) or a salt thereof to react with a compound represented by the general formula (V).
In carrying out the reaction, in order to progress the reaction smoothly, it is advantageous in some cases to use the substituted amine (VI) in excess amount or to carry out the reaction in the presence of N-methylmorpholine, trimethylamine, triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, DMAP, picoline, lutidine, collidine, 1,8-bistrimethylaminonaphthalene, DBU or the like organic base or potassium carbonate, sodium carbonate, calcium carbonate, sodium bicarbonate, sodium hydroxide, cesium carbonate or the like inorganic base. Pyridine or the like can also be used as the solvent. In some cases, it may be effective to use some organometallic catalysts to accelerate a reaction. Though it varies depending on the used substrate and conditions, the reaction is generally carried out in an inert organic solvent including dichloromethane, dichloroethane, chloroform and the like halogenated hydrocarbons, benzene, toluene, xylene and the like aromatic hydrocarbons, ether, tetrahydrofuran and the like ethers, ethyl acetate and the like esters, ethanol, methanol and the like alcohol solvents, acetonitrile, DMF, N,N-dimethylacetamide, N-methylpyrrolidone, N,N-dimethylimidazolidinone, dimethyl sulfoxide and the like, under cooling, under cooling to room temperature or under room temperature to heating, depending on the reactive derivative.
Fourth production method 
(Symbols in the formula are as defined in the foregoing.)
This production method is a method in which the compound (I) of the invention is produced by the alkylation or acylation of a compound of the invention represented by the general formula (Ixe2x80x2: R4xe2x95x90H).
In this reaction, it is possible to use an alkylation agent such as methyl iodide, ethyl iodide, benzyl bromide or the like alkyl halide, dimethyl sulfate or the like sulfuric ester and methane sulfonate, methyl trifluoromethanesulfonate or the like sulfonate. Alternatively, an acylation agent such as acetyl chloride or the like acid chloride or acetic anhydride or the like acid anhydride is used. In this case, triethylamine, diisopropylethylamine, pyridine, lithium diisopropylamine, sodium hexamethyldisilazide or the like organic base or sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate, sodium hydroxide, sodium hydride or the like inorganic base may be used.
The reaction is generally carried out in an inert organic solvent including dichloromethane, dichloroethane, chloroform and the like halogenated hydrocarbons, benzene, toluene, xylene and the like aromatic hydrocarbons, ether, tetrahydrofuran and the like ethers, ethyl acetate and the like esters, DMF, N,N-dimethylacetamide, dimethyl sulfoxide and the like, under cooling, under cooling to room temperature or under room temperature to heating, depending on the reactive derivative.
Fifth production method 
(Symbols in the formula are as defined in the foregoing.)
This production method is a method in which the compound (I) of the invention is produced by cyclization of a compound represented by the general formula (VII).
In this reaction, aldehyde or ketone and acetal, ketal, thioketal or the like carbonyl equivalent compound are used in the cyclization. In general, an acidic condition or a basic condition can be used in the reaction which is generally carried out in an inert organic solvent including dichloromethane, dichloroethane, chloroform and the like halogenated hydrocarbons, benzene, toluene, xylene and the like aromatic hydrocarbons, ether, tetrahydrofuran and the like ethers, ethyl acetate and the like esters, DMF, N,N-dimethylacetamide, dimethyl sulfoxide and the like, under cooling, under cooling to room temperature or under room temperature to heating, depending on the reactive derivative. Acetic acid, trifluoroacetic acid or the like organic acid is particularly suitable.
The compound of the invention synthesized in accordance with the above methods can be converted into other compounds of the invention by the conversion of functional groups and the like by using known reactions, and some of them were described in Examples.
The thus produced compound of the invention is isolated and purified as its free form, a salt thereof, a hydrate thereof, a solvate thereof or as a polymorphic substance. A salt of the compound (I) of the invention can also be produced by subjecting it to a usual salt formation reaction.
The isolation and purification are carried out by employing extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography and the like usual chemical operations.
Various types of isomers can be selectively synthesized by using appropriate starting materials, reagents or reaction conditions, or separated by making use of the difference in physical properties among isomers. For example, each optical isomer can be prepared as a stereochemically pure isomer by selecting appropriate materials or separated by an optical resolution of racemic compounds (e.g., a general method in which they are converted into diastereomer salts with an optically active base and then subjected to optical resolution).
A pharmaceutical preparation which contains one or more of the compounds of the invention or salts thereof as the active ingredient is prepared using carriers, fillers and other additives generally used in the preparation of medicaments.
It may be administered either by oral administration through tablets, pills, capsules, granules, powders, solutions or the like, or by parenteral administration through intravenous injection, intramuscular injection and the like injections, suppositories, percutaneous preparations and the like. Its dose is optionally decided by taking symptoms, age and sex of the patient to be treated and the like into consideration, but generally, it is approximately from 0.01 to 50 mg per day per adult in the case of oral administration or approximately from 0.001 to 5 mg per day per adult in the case of parenteral administration, and the daily dose is administered once a day or by dividing it into 2 to 4 doses per day.
The solid composition for use in the oral administration according to the invention is used in the tablets, powders, granules and the like forms. In such a solid composition, one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, metasilicate or magnesium aluminate. In the usual way, the composition may contain additives other than the inert diluent, which include a lubricant such as magnesium stearate, a disintegrating agent such as calcium cellulose glycolate, a stabilizing agent such as lactose and a solubilization assisting agent such as glutamic acid or aspartic acid. As occasion demands, tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like.
The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contains a generally used inert diluent such as purified water or ethanol. In addition to the inert diluent, this composition may also contain auxiliary agents such as a moistening agent and a suspending agent, as well as a sweetener, a flavor, an aromatic and an antiseptic.
The injections for parenteral administration includes aseptic aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the diluent for use in the aqueous solutions and suspensions include distilled water for injection use and physiological saline. Examples of the diluent for use in the non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, olive oil or the like plant oil, ethanol or the like alcohol, polysorbate 80 (trade name) and the like. Such a composition may further contain auxiliary agents such as an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent (e.g., lactose) and a solubilization assisting agent (e.g., glutamic acid or aspartic acid). These compositions are sterilized for example by filtration through a bacteria retaining filter, blending of a germicide or irradiation. Alternatively, they may be used by firstly making into sterile solid compositions and dissolving them in sterile water or a sterile solvent for injection use prior to their use.